IgA is the predominant Ig isotype in mucosal secretions of most mammalian species and is thus ideally localized to prevent pathogen entry. We took advantage of the large quantities of mucosal tissues, including lymph nodes and Peyer's patches in cattle to develop a cDNA library to probe for factors that regulate IgA expression. We identified a novel factor in the bovine, which impacts IgA production in vito and designated the factor, IgA Inducing Protein or IGIP. The general goal of this two-year innovative proposal is to extend our studies of this novel factor to humans and to elucidate the mechanisms by which IGIP influences IgA production. Our working hypothesis for the project is that interstitial dendritic cell derived- IGIP is conserved across mammalian species and is an essential component of T-dependent and independent pathways for induction of IgA-expressing cells. We also hypothesize that altered IGIP regulation in dendritic cells and/or B cells is a factor in selective IgA deficiency. The specific aims that will test this hypothesis are: 1) Use an established in vitro model to determine the role of IGIP in differentiation of IgA-expressing human B cells; 2) Identify the cellular sources of IGIP transcripts and protein in peripheral blood leukocytes including dendritic cells, T cells, B cells and monocyte/macrophages from normal individuals; 3) Compare the expression of IGIP transcripts and protein and the responsiveness to IGIP of peripheral blood leukocytes from patients with selective IgA deficiency. The proposed studies will be the first to establish the mechanism(s) by which a unique, recently identified factor acts in concert with known factors such as TGF-beta or IL-10 to promote IgA responses and should help clarify the role of human DC in the regulation of the IgA responses. In addition, the proposed studies will begin to examine determine the potential relationship between IGIP and clinical abnormality in IgA production. [unreadable] [unreadable]